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Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia

2020-11-19Journal article Restricted access
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dc.contributor.authorSalas-Huetos, Albert
dc.contributor.authorTüttelmann, Frank
dc.contributor.authorWyrwoll, Margot J.
dc.contributor.authorKliesch, Sabine
dc.contributor.authorLopes, Alexandra M.
dc.contributor.authorGonçalves, João
dc.contributor.authorBoyden, Steven E.
dc.contributor.authorWöste, Marius
dc.contributor.authorHotaling, James M.
dc.contributor.authorGEMINI Consortium
dc.contributor.authorNagirnaja, Liina
dc.contributor.authorConrad, Donald F.
dc.contributor.authorCarrell, Douglas T.
dc.contributor.authorAston, Kenneth I.
dc.date.accessioned2021-03-07T16:30:22Z
dc.date.available2021-03-07T16:30:22Z
dc.date.issued2020-11-19
dc.descriptionGEMINI Consortium: Donald F Conrad, Kenneth I Aston, Douglas T Carrell, James M Hotaling, Liina Nagirnaja, Timothy G Jenkins, Moira K O'Bryan, Rob McLachlan, Peter N Schlegel, Michael L Eisenberg, Jay I Sandlow, James F Smith, Puneet Kamal, Carole Ober, Mark Sigman, Kathleen Hwang, Emily S Jungheim, Kenan R Omurtag, Alexandra M Lopes, Filipa Carvalho, Susana Fernandes, Alberto Barros, João Gonçalves, Maris Laan, Margus Punab, Ewa Rajpert-De Meyts, Niels Jørgensen, Kristian Almstrup, Csilla G Krausz, Keith A Jarvi, Davor Jezekpt_PT
dc.descriptionCorrection to: Disruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermia. Salas-Huetos A, Tüttelmann F, Wyrwoll MJ, Kliesch S, Lopes AM, Gonçalves J, Boyden SE, Wöste M, Hotaling JM; GEMINI Consortium, Nagirnaja L, Conrad DF, Carrell DT, Aston KI. Hum Genet. 2021 Jan;140(1):229. doi: 10.1007/s00439-020-02244-1.pt_PT
dc.description.abstractNon-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed the NOA phenotype. We performed whole-exome sequencing in three affected brothers with NOA, their two unaffected brothers and their father, and identified compound heterozygous frameshift variants (one novel and one extremely rare) in Telomere Repeat Binding Bouquet Formation Protein 2 (TERB2) that segregated perfectly with NOA. TERB2 interacts with TERB1 and Membrane Anchored Junction Protein (MAJIN) to form the tripartite meiotic telomere complex (MTC), which has been shown in mouse models to be necessary for the completion of meiosis and both male and female fertility. Given our novel findings of TERB2 variants in NOA men, along with the integral role of the three MTC proteins in spermatogenesis, we subsequently explored exome sequence data from 1495 NOA men to investigate the role of MTC gene variants in spermatogenic impairment. Remarkably, we identified two NOA patients with likely damaging rare homozygous stop and missense variants in TERB1 and one NOA patient with a rare homozygous missense variant in MAJIN. Available testis histology data from three of the NOA patients indicate germ cell maturation arrest, consistent with mouse phenotypes. These findings suggest that variants in MTC genes may be an important cause of NOA in both consanguineous and outbred populations.pt_PT
dc.description.sponsorshipThis work was supported in part by funding from the National Institutes of Health (R01HD078641) and the German Research Foundation (Clinical Research Unit ‘Male Germ Cells: from Genes to Function’, DFG CRU326).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHum Genet. 2021 Jan;140(1):217-227. doi: 10.1007/s00439-020-02236-1. Epub 2020 Nov 19.pt_PT
dc.identifier.doi10.1007/s00439-020-02236-1pt_PT
dc.identifier.issn0340-6717
dc.identifier.urihttp://hdl.handle.net/10400.18/7353
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00439-020-02236-1pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectNon-obstructive azoospermia (NOA)pt_PT
dc.subjectMale Infertilitypt_PT
dc.subjectAzoospermiapt_PT
dc.subjectTERB1pt_PT
dc.subjectTERB2pt_PT
dc.subjectMAJINpt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleDisruption of human meiotic telomere complex genes TERB1, TERB2 and MAJIN in men with non-obstructive azoospermiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage227pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage217pt_PT
oaire.citation.titleHuman Geneticspt_PT
oaire.citation.volume140pt_PT
person.familyNameGonçalves
person.givenNameJoão
person.identifier.ciencia-id5710-1FAE-5FAB
person.identifier.orcid0000-0001-9359-8774
person.identifier.ridL-2265-2014
person.identifier.scopus-author-id55934387500
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication6bbd19e6-ea9c-4502-b972-ec6997e9c481
relation.isAuthorOfPublication.latestForDiscovery6bbd19e6-ea9c-4502-b972-ec6997e9c481

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